​Kembara Xtra - Medicine - Narcolepsy

​Kembara Xtra - Medicine - Narcolepsy
The neurologic sleep disorder narcolepsy is characterized by excessive daytime sleepiness (EDS) and may be accompanied by cataplexy (sudden loss of muscle control), hypnagogic hallucinations (vivid perceptual experiences during sleep), hypnopompic (vivid perceptual experiences during wakefulness), or sleep paralysis (temporary paralysis of the muscles allowing for movement or speech during the transition from sleep to wakefulness).
There are primarily two varieties of narcolepsy, according to the American Academy of Sleep Medicine: type 1 (60–70%), also known as narcolepsy with cataplexy, and type 2, also known as narcolepsy without cataplexy. No treatment, only symptomatic relief


Epidemiology Incidence: Bimodal distribution; age of onset peak at 15 years, then again at 35 years; affects 0.03 to 0.16% of the general population globally.
Male is more prevalent than female (1.6:1) 5% of cases are familial (1) African Americans are more likely to arrive younger and without cataplexy.
Prevalence
Narcolepsy type 1 affects 25 to 50 persons per 100,000. Narcolepsy type 2 affects 20 to 34 persons per 100,000.


Pathophysiology and Etiology 

mostly brought on by the atrophy of orexin (hypocretin)-producing hypothalamic neurons. Postmortem investigations reveal a loss of these neurons of 85% in type 1 and 33% in type 2, respectively.
Orexin, which activates the reticular activating system and prevents fast eye movement, is essential for promoting wakefulness. Neurodegeneration may result from an autoimmune process that is most likely triggered by environmental variables (often happens in late spring) or viruses (such influenza A or group A Streptococcus).
Additionally, it appears that changes in the amount of L-PGDS (lipocalin-type prostaglandin D synthase) contribute to EDS in narcolepsy.
● Third edition of the International Classification of Sleep Disorders (ICSD-3) classification: Sleep apnea
- Type 1 narcolepsy - Type 2 narcolepsy - Narcolepsy brought on by illnesses
Genetics
 Usually sporadic, but more common among families with a favorable history: 1-2% of the index case's first-degree relatives (10–40 times the general population) Human leukocyte antigen (HLA) DQB1*0602 is expressed by 40–50% of patients with narcolepsy type 2 and is present in 98% of patients with narcolepsy type 1. In the general population, HLA DQB1*0602 is prevalent in 12–30% of cases.
12% of Asians, 25% of Whites, and 38% of African Americans have the autosomal recessive inheritance pattern.

Risk factors include: Obesity; Head Trauma; Infectious Disease of the Central Nervous System; Anesthesia; Psychological Stress; Positive Family History; Recent Influenza A, Streptococcal Infection, or H1N1 Vaccination (there is currently no evidence that COVID causes narcolepsy)


Accompanying Conditions 
obesity, anxiety, and obstructive sleep apnea (OSA) (up to 25%).

The five most typical symptoms of EDS, which include the classic pentad, cataplexy, sleep paralysis, hypnagogic/hypnopompic hallucinations, and disturbed nocturnal sleep, are as follows: Only 10–20% of people have all five.
EDS and insomnia (the cardinal symptom) - EDS is always present in individuals and is typically the first symptom to appear.
- EDS must occur virtually daily for at least three months in order to receive an ICSD-3 classification for type 1 or type 2.
- Patients may report taking rejuvenating naps during the day, with the possibility of EDS returning in 1–2 hours.
- Momentary sleep attacks (seconds) while engaging in stimulating activities like driving and walking  Cataplexy (patients 65–75%)
- Most commonly related to type 1 narcolepsy (1) - Sudden, brief (seconds to minutes), entire or partial bouts of loss of motor tone (buckling of knees, head dipping, sagging of jaw, weakness in arms, slurred speech, grimacing of the face, etc.), brought on by powerful emotions (such as laughter, rage, or panic) - Memory and consciousness are not hampered.
Sleep paralysis is the temporary inability to move, speak, or open one's eyes during the process of falling asleep or upon awakening (lasting several minutes). - Breathing may be challenging during the incident because the paralyzed intercostal muscles make the chest seem heavier.
- Patients are able to remember the incident and are aware of their surroundings.
- Found in 67% of narcolepsy patients with cataplexy and 49% of narcolepsy patients without cataplexy. Hypnagogic or hypnopompic hallucinations: - Patients with type 1 narcolepsy report vivid dream-like experiences between 30 and 60 percent of the time, either as they awaken (hypnopompic hallucinations) or as they begin to fall asleep (hypnagogic).
Rather than hypnagogic hallucinations, hypnopompic ones are more suggestive of narcolepsy.
- Visual, tactile, or auditory hallucinations are most common.
- Hallucinations that are characteristic include being assaulted by animals or sensing the presence of another person.
- These are also experienced by 15% of people with type 2.
 Additional reported history
- Nighttime incontinence and fragmented sleep (problems sustaining sleep rather than difficulty beginning sleep). - Increased periodic limb movements - Depression, anxiety, and social phobia - Retrograde amnesia
- Acting out dreams - Gaining weight as the condition progresses


clinical assessment 
Unremarkable, but thorough examination may help rule out alternative explanations In a cataplexy episode, deep tendon reflexes are either reduced or nonexistent.

Multiple Diagnoses 

Despite the fact that the majority of people with EDS do not have narcolepsy, it affects 4 to 28% of the general population: SARS (sleep apnea syndromes)
Syncope and epileptic seizures
Idiopathic hypersomnia (5–10% of EDS cases)  Psychiatric (substance abuse/withdrawal, bipolar disorder, and depression) iatrogenic/secondary to medication (benzodiazepines, barbiturates, opioids, antihistamines, -blockers, and some antipsychotics, antidepressants, and anticonvulsants); sleep-related movement disorders (restless leg syndrome, periodic limb movements of sleep); poor sleep hygiene and habits leading to sleep deficit and chronic sleep deprivation; circadian rhythm disorders (jet lag, shift work, delayed or advanced sleep phase disorders); cataplex Menstrual-related hypersomnia, Parkinson's disease-related hypersomnia, and stroke (partially cataplexic speech and sagging facial muscles) are all examples of hypersomnia.
Child Safety Considerations
Before the age of five, narcolepsy is rare. OSA, poor sleep hygiene, and the higher sleep requirements in the early years of life are more frequently to blame for EDS. Age-related sleep recommendations are as follows: newborns need 16 to 18 hours of sleep each day, toddlers need 11 to 12 hours, school-age kids and teens need 10 hours, and adults need 7 to 8 hours. 20 to 40 lb of excessive weight gain in children is possible (2). EDS, sleep paralysis, and cataplexy symptoms may continue longer in children than in adults.

Laboratory Results 
First, make sure the patient is sleeping for 6 hours every night for at least 7 to 14 days.
Prerequisites for a valid multiple sleep latency test (MSLT) include a normal polysomnography (PSG), a standardized sleep routine for seven days, and a drug-free period of at least two weeks. To rule out other potential causes of EDS, an overnight PSG is the first line of defense.
- MSLT: conducted the day following PSG if at least 6 hours of sleep were obtained and PSG did not reveal any sleep disorders.
 Four to five 20-minute naps spaced two hours apart.
Positive results include shorter mean sleep latency (8 minutes) and quick onset of REM (15 minutes) in at least two out of five nights (including baseline PSG). Repeat the test if the MSLT is negative but there is a significant clinical suspicion.
 Antidepressants and stimulants ought to be stopped at least two weeks beforehand.
 Scoring tools - Epworth Sleepiness Scale (ESS): scored 0 to 24; >10 suggests a sleep disorder rather than general fatigue; useful for identifying treatment response. - The weariness Severity questionnaire, a nine-item questionnaire that assesses the level of weariness (and aids in separating it from sleep disorders). - Stanford Sleepiness Scale: Patients choose one of seven phrases that best sums up their degree of alertness, focus, and drowsiness. The statements 4 through 7 might point to oversleeping.
- Narcolepsy Severity Scale: a 15-item scale to evaluate the frequency, seriousness, and effects of narcolepsy type 1 symptoms.
- Pediatric scoring tools: Pediatric Daytime Sleepiness Scale and Epworth Sleepiness Scale for Children and Adolescents (a modified version of ESS). Tests in the Future & Special Considerations
HLA typing, especially in children. Lumbar puncture for orexin level; 110 pg/mL or fewer in the cerebrospinal fluid (CSF) is symptomatic of narcolepsy. It lacks specificity and is supportive of the diagnosis Diagnostic Tests/Other
Type 1 narcolepsy, EDS every day for three months, and one of the following:
Cataplexy with a positive MSLT Low CSF orexin level 110 pg/mL or 1/3 of mean values in healthy persons Narcolepsy type 2 All of the aforementioned (with or without cataplexy) with a normal CSF orexin level  It is an exclusionary diagnosis.

Management 
The aim of medications is to reduce EDS and cataplectic episodes, not to cure.
If drug therapy is employed, it should be combined with a variety of behavioral tactics.
 Good sleeping habits and a consistent sleep routine.
 Strategic 20-minute naps might be beneficial.
 Steer clear of stimulants including alcohol, large meals, coffee, and nicotine.
Cataplectic episodes may be quickly stopped by actions like changing one's thinking, tensing up one's muscles, or pressing against a solid support.
Keeping your body at a higher temperature and consuming warm foods and beverages may help you stay awake.
 Take safety precautions, especially when operating a vehicle.
Patients who go untreated have a 10-fold higher chance of accidents.

First Line of Medicine
Modafinil (Provigil) EDS:
For EDS that is mild to moderate
Use 200 mg/day to affect the hypothalamic dopaminergic, adrenergic, and histaminergic receptors. Start with 100 mg; the maximum daily dose is 400 mg; the half-life is 15 hours; adverse effects include headache, GI distress, and accelerated metabolism of oral contraceptives with less rebound insomnia; tolerance is restricted.  Use caution when using oral contraceptives because it reduces their effectiveness and may cause tachycardia in people with heart disorders. Children's use is not FDA-approved
- Nuvigil (armodafinil):
 Modafinil's enantiomeric version, which has the same half-life but a milder side-effect profile Less side effects compared to modafinil: headache, xerostomia, Stevens-Johnson syndrome, and toxic epidermal necrolysis. Dose: 150 to 250 mg per morning. Children's use is not FDA-approved
- FDA-approved for both cataplexy and narcolepsy is pitolisant (Wakix). Up to 35.6 mg of a dose showed effectiveness (4).
- Clarithromycin: It works on the GABA-A receptor and can treat hypersomnia if other medications are ineffective.
Start with a 2-week trial dose of 500 mg BID.
Negative impact: GI discomfort Levothyroxine (25mcg/day) improved EDS in euthyroid patients without cataplexy in 12 weeks.
- Xyrem (sodium oxybate):
Only treatment FDA-approved for both cataplexy and EDS. For those seven years and older now.
For instances that are moderate to severe
The best option for enhancing overnight sleep is caffeine. The recommended dosage is 6 to 9 g/day divided BID; the maximum dose is 9 g/day. It may take 8 to 12 weeks for a full effect.
Is a medication with rape potential; potential for abuse
 Could make OSA patients' sleep breathing problems worse
Coma could result from an overdose.
- Sunosi Solriamfetol:
Start with 75 mg qD, then raise the dose every three days based on response to a maximum of 150 mg/day, which is contraindicated with concurrent or recent MAO-I usage.
Potential for abuse: Exercise caution around patients who have used drugs in the past.
The tricyclic antidepressants
 Protriptyline: daily dosing range: 5 to 60 mg. Reduce the dose.
Clomipramine dosage ranges from 25 to 75 mg per day. Anticholinergic side effects include impotence, drowsiness, dry mouth, and urine retention. - Inhibitors of the serotonin-norepinephrine reuptake
Venlafaxine dosage ranges from 75 to 300 mg daily. Start with 37.5 mg and go up to 375 mg per day. To stop, reduce the dosage.
Fluoxetine: dosage: 20 to 80 mg/day; suppresses REM sleep; not FDA-approved; patient may get tolerant to anticataplectic medications and experience rebound cataplexy when a medication is stopped. Tapering off means ending.
 Though less frequently treated than EDS and cataplexy, auxiliary symptoms (such as hypnagogic hallucination and sleep paralysis) are still useful when symptoms are troubling.

Next Line
If the first treatment option fails or the patient cannot tolerate it, EDS - amphetamines are employed. Methylphenidate (Ritalin): initial dose 5 to 10 mg/day divided BID or TID; max dose 60 mg/day; short acting, most potent amphetamine currently available; can be combined with modafinil and armodafinil; Dextroamphetamine: initial dose 10 mg/day; can increase by 10 mg qwk to a max dose 60 mg/day divided BID or TID; contraindicated in patients with hypertension Instead of increasing the dose if the patient becomes tolerant to stimulants, switch medications or take a drug break.
 Addictive; excessive doses are linked to mental disorders, arrhythmias, and repeated hospitalizations. Selegiline, a selective MAO-B inhibitor, is an anticataplectic that is beneficial for EDS; the recommended dosage is 20 to 40 mg twice a day, in the morning and the afternoon. The medication starts to lose selectivity at doses greater than 20 mg, necessitating a low-tyramine diet.
Temazepam, a benzodiazepine, is effective in reducing daytime sleepiness and preventing numerous nocturnal awakenings. Take 15 to 30 mg at night once.

Referral 
Neurology referrals may be helpful for patients who are unresponsive to their primary medications and have severe cataplexy.

Follow-up patient monitoring is recommended for patients taking medication and involves routine follow-up visits as well as frequent blood pressure measurements to assess treatment effectiveness and symptom control.

Diet 
Those taking Selegiline at high doses (>20 mg) must follow a low-tyramine diet.

Prognosis 
The disease narcolepsy lasts a lifetime. Approximately 60–80% of patients saw improvements. With time, symptoms can get worse. After menopause, symptoms in women can get better.

Complications 
Binge eating is more common in cataplexy patients.